Judge blocks FDA bid to allow generic Precedex

The US District Court for Maryland on August 19 granted Hospira a temporary restraining order (TRO) against FDA, the day after the agency determined that potential generic competitors of the company's injectable sedation drug Precedex could be approved if they avoided protected new indications in the innovator's labeling.

FDA, which has for decades been aggressively pro-generic, has been allowing so-called patent “use codes” to be published alongside brand patents in its bioequivalence directory known as the Orange Book.

The use code tells the agency the language that must be removed from a branded drug's label to ensure that it does not appear on a generic imitator's label and thereby infringe on any patented use. There have been allegations that brand companies manipulate these use codes more broadly than patent claims, to stop so-called “skinny labeling” of drugs protected only by use patents.

In granting the TRO—a tacit prediction that it will become a permanent injunction—the court sided with Hospira's argument that the FDA determination conflicted with a recent US Supreme Court decision in Caraco Pharm. Labs., Ltd. v. Novo Nordisk A/S. This stated that the agency could not approve a generic if its proposed label overlaps at all with the brand's use code.

“At this juncture,” Judge George J. Hazel wrote, “the court therefore finds that FDA's decision was at odds with relevant authority. Furthermore, to now permit FDA to approve generic versions of Precedex on the basis that it can approve [generic applications] for broad, general indications that overlap with a protected method of use would be tantamount to a change of the rules. Such a change would require FDA to employ the formal rulemaking procedures of the Administrative Procedures Act, which it indisputably did not do.”

This has become a broad basis for concern among those who closely watch FDA. They perceive a growing tendency by the agency to use less formal means to avoid the lengthy and burdensome requirements of formal rulemaking.

Primarily, these requirements demand public notice in the daily Federal Register, receipt and review of public comments, and prior notice of ultimate decisions to affected parties, along with reasonable opportunity to appeal or file suit in court.

In the Precedex matter, Hospira reacted with lightning speed. The day after FDA's determination the company was in court, and late that night, FDA was stopped, at least for 14 days (until September 2), which is the time limit on a TRO.

Its speed was necessary. In the two days after FDA's determination, two generic companies (Mylan and Par) rushed Precedex competitors into the market that subsequently had to be halted by the court—although an actual recall ordered in the TRO was withdrawn.

Can FDA persuade the court not to grant a permanent injunction? The case is being watched with intense interest, especially by the brand-name drug industry, because of its implications for all drugs, not just Precedex generics.

In its August 18 determination allowing label “carve-outs” across the board for any generic meeting the determination's liberal conditions, FDA concluded that regardless of whether the brand's use code has been changed after approval (as Precedex's had been), “the agency can approve (a generic) that submits a ‘Section viii' statement and omits labeling that discloses the protected use … FDA further concludes that such omissions do not render the drug less safe or effective for the remaining non-protected conditions of use.”

FDA had been struggling with what to do about patent use codes that are narrower than the approved indication on the label. Under agency policies, a narrow use code that overlaps a broad indication can only be carved out by omitting the entire indication.

Earlier this year, the agency asked stakeholders whether an approved indication can be subdivided into inherently authorized sub-indications to match the use code submitted by the brand so that generics may carve it out of their label.

FDA says its determination in allowing a labeling carve-out if the proposed ANDA labeling does not disclose the protected use is consistent with previous determinations.

“For generic tramadol, for example, FDA allowed [generics] to carve out a protected titration schedule that was based on a study analyzing the narrow question of the tolerability of the drug in patients who had previously been shown to be tramadol-intolerant and be approved with a broad indication for ‘management of moderate to moderately severe pain,'” it says.

“In that decision, FDA concluded that information specific to the titration schedule could be carved out without rendering the product less safe or effective for the non-protected conditions of use, even though that tramadol-intolerant sub-population may be part of the larger population for which the product is prescribed.”

But all that was FDA essentially talking to itself, discounting any industry objections and plowing ahead with what it wants to do—a practice many close observers say they see increasing.

Most recently, in the medical device arena, FDA was criticized for essentially the same thing—publishing guidance documents that could have the effect of a regulation bringing exempt clinical laboratories into FDA's definition of regulated device manufacturers, in order to regulate their retailing of laboratory developed tests.